The Women's Health Initiative (WHI) trial has demonstrated that use of postmenopausal estrogen plus progestin therapy reduces risk of colorectal cancer in women, but use of estrogen alone among women with prior hysterectomy has no effect. These data suggest a complex effect of estrogen and progesterone on colorectal carcinogenesis. However, the underlying mechanisms by which estrogen and progesterone affect the development of colorectal cancer are poorly understood. Applying state-of-the-art genotyping technology and statistical methods, we will evaluate functional variants and determine the structure of haplotypes in 11 candidate genes important to estrogen and progesterone metabolism, and investigate their relationships with risk of colorectal cancer in the WHI observational study (OS) cohort, an ethnically diverse population. Specific studies will focus on genes encoding estrogen and progesterone receptors (ESR1, ESR2, and PGR) and enzymes responsible for local estrogen concentrations and the conversion of progesterone to estrogens via androgens (HSD17B1, HSD17B2, HSD17B4, CYP19A1, and CYP17A1) and for estrogen catabolism (CYP1A1, CYP1B1, and COMT). A total of 800 incident colorectal cancer cases and their two matched controls will be identified in the WHI-OS cohort of postmenopausal women with achieved blood samples and free of cancer at baseline. The WHI-OS cohort has a large number of confirmed cases of colorectal cancer and is well characterized with respect to use of postmenopausal hormone therapy and environmental exposures, thus providing an extraordinary opportunity to examine the main effects of gene variants and their interactions with use of combination hormone therapy vs. estrogen alone in relation to colorectal cancer risk. We also will explore interactions among these candidate genes. Hypotheses proposed in this application are novel, as the relations between estrogen and progesterone-related gene variants and risk of colorectal cancer are largely unexplored. Findings from this proposed study will help elucidate the roles of estrogen and progesterone in colorectal carcinogenesis, the differences between the effects of postmenopausal estrogen plus progestin therapy vs. estrogen alone on colorectal cancer risk observed in the WHI trial, and may suggest future targets for interventions to prevent colorectal cancer. Several unique features of the WHI-OS cohort, including its prospective design, diverse ethnic and social composition, large sample size, long duration, high follow-up rates, availability of stored blood specimens, and comprehensive covariate information, make this cohort a valuable and exceptional resource for the etiologic investigation of colorectal cancer.